Keywords
Breast carcinoma - distance from skin - nodal status
Introduction
Breast cancer is the most common type of cancer in females worldwide, and the burden
is increasing day by day in both developed and developing countries. According to
National cancer registry in India, breast cancer is now leading cancer in females
surpassing the cervical cancer, at both urban and rural locations across India.[1]
The success of treatment is based on early detection and proper staging. Tumor size
and axillary nodal status are still vital prognostic indicators of breast cancer.
The Large size of tumor and increased number of involved nodes are associated with
poorer prognosis and increased rate of recurrences and mortality.[2]
According to literature, various other prognostic markers are age, vascular invasion,
hormonal receptors status, menopausal status, histological grade, nuclear grade, lymphovascular
invasion, DNA ploidy, and various tumor markers. However, axillary lymph node status
is still the single most important prognostic indicator in breast cancer.[3],[4]
The seventh edition of tumor node metastasis staging in breast cancer by American
Joint Committee on Cancer (AJCC) includes the size of the tumor and the nodal status
as the most important prognostic factors. The nodal status is divided into three N
stages according to AJCC guidelines: N1 (1–3 nodes positive), N2 (4–9 nodes positive),
and N3 (more than 9 nodes positive).[5]
Previous studies have demonstrated that lymph node status correlates well with the
tumor size, i.e., larger the tumor size, worse is the prognosis. According to literature,
it has been demonstrated that histologic grading, lymphovascular invasion, and location
of the tumor also affects the nodal positivity.[6],[7],[8]
Most of the lymphatics drain the breast through the cutaneous lymphatic drainage system
which consists of a superficial plexus of channels that lie within the dermis and
a deeper network of lymphatic channels that runs with the mammary ducts in the subareolar
area. Hence, any tumor close to these structures has access to abundant lymphovascular
network and has an increased chance to metastasize.[9] Thus, we proposed that tumors close to the skin should have a higher rate of axillary
lymph node metastasis at diagnosis. The aim of the present study was to know whether
the distance from overlying skin or nipple and areola increase the risk of lymph nodal
metastasis. There are only a handful of studies done on the correlation of skin distance
with nodal status and to the best of our knowledge; this will be the first study from
India demonstrating this factor.
Materials And Methods
This was a retrospective analysis of all operated case of breast cancer (includes
lumpectomy with Axillary dissection and mastectomy) performed at a tertiary care cancer
institute over a period of 4 years (January 2013 to November 2016). A total of 200
cases were studied. All the cases with only ductal carcinoma in situ component and
previous history of surgery, hormonal therapy, previous radiotherapy, or neoadjuvant
chemotherapy as well as cases in male sex were excluded from the study. Only cases
with a primary diagnosis of infiltrating mammary carcinoma operated either as lumpectomy
with axillary dissection or modified radical mastectomy was included in this study.
The data were retrieved from the reports stored at histopathology section of department
of pathology. The data were recorded from the reports available to note the site,
size, grading, and distance of tumor from skin and nodal status of the disease. The
data were tabulated and analyzed. Slides of the cases were reviewed in case of any
doubt. All the variables were analyzed and correlation with nodal metastasis was studied.
Location of the tumors in the breast was noted and tumors were categorized based on
location as located in upper outer quadrant (UOQ), upper inner quadrant (UIQ), lower
outer quadrant (LOQ), lower inner quadrant (LIQ), and retro-areolar region. Tumors
were separated based on AJCC as T1/2/3/4 and N1/2/3. We also segregated tumors with
T2 size as T2/4 where skin was ulcerated or microscopically involved. Tumors with
T3 size where tumor was microscopically infiltrating the epidermis were also segregated
as T3/4. This was done to know whether smaller tumor (T2 size) infiltrating the skin
grossly or microscopically and T3 tumors with microscopic skin invasion have more
chances of metastasis to lymph nodes. Tumors were graded based on the “Nottingham
combined histologic grade (Elston-Ellis modification of Scarff-Bloom-Richardson grading
system).”[10]
Tumor grade was compared with the nodal status of the disease and was tabulated and
evaluated. Patients were divided into two groups according to breast cancer distance
from the skin: <3 mm group and >3 mm group. This was based on the superficial lymphatic
drainage of the breast as described in literature is located from the skin to a 3
mm depth.[11],[12]
Results
In this study, the woman in 5th decade had increased incidence of breast cancer (133
cases; 66.5%). The left side of breast was most commonly involved (68.7%), and UOQ
was most frequently involved (93 cases; 68.8%).
On correlating site of the lesion with lymph node involvement [Table 1], the N2 and N3 nodal status were most commonly seen with tumors located in UOQ (61.5%)
followed by LOQ (12%) and retro-areolar region (12%). While 36.8% of tumors in UIQ
and 41.6% in LIQ showed N2/N3 nodal status. N1 nodal status was seen in 22.5% of cases
with the most common location being UOQ.
Table 1
Correlating site of tumor and nodal positivity
|
Tumor based on location
|
N0
|
N1
|
N2
|
N3
|
Total cases
|
Total nodes positive (%)
|
Total nodes negative (%)
|
|
Upper outer quadrant
|
30
|
35
|
38
|
20
|
123
|
93 (75.5)
|
30 (24.5)
|
|
Upper inner quadrant
|
10
|
2
|
5
|
2
|
19
|
9 (47.3)
|
10 (52.6)
|
|
Lower outer quadrant
|
10
|
4
|
8
|
2
|
24
|
14 (58.3)
|
10 (41.7)
|
|
Lower inner quadrant
|
9
|
1
|
0
|
0
|
10
|
1 (10)
|
9 (90)
|
|
Retro-areolar
|
6
|
3
|
10
|
5
|
24
|
18(75)
|
6 (25)
|
|
Total
|
65
|
45
|
61
|
29
|
200
|
135 (67.5)
|
65 (32.5)
|
Out of total 200 cases, 5.5%, 58.5%, and 22% tumors belong to T1, T2, and T3, respectively
[Table 2]. The most common T size showing N2 and above nodal status was T2 (19.5%) followed
by T3 (12.5%) and T1 (0.5%) excluding cases with T4 and T2/T3 with skin invasion.
Table 2
Correlating size of tumor and nodal positivity
|
Tumor based on tumor size
|
N0
|
N1
|
N2
|
N3
|
Total cases
|
Total nodes positive (%)
|
Total nodes negative (%)
|
|
T1
|
7
|
3
|
1
|
0
|
11
|
4 (33.3)
|
7 (66.7)
|
|
T2
|
48
|
30
|
25
|
14
|
117
|
69 (58.9)
|
48 (41.1)
|
|
T2/4
|
0
|
0
|
3
|
1
|
4
|
4(100)
|
0
|
|
T3
|
9
|
10
|
14
|
11
|
44
|
35 (79.5)
|
9 (20.5)
|
|
T3/4
|
0
|
1
|
9
|
3
|
13
|
13(100)
|
0
|
|
T4
|
1
|
1
|
8
|
1
|
11
|
10 (90.9)
|
1 (9.09)
|
|
Total
|
65
|
45
|
60
|
30
|
200
|
135 (67.5)
|
65 (32.5)
|
N1 nodal status was seen in 22.5% of cases and is seen with all sizes (T1-6.6%, T2-66.6%,
T3-22.4%) excluding T4 and T2/T3 with skin invasion.
In this study, a distance of skin from the tumor was calculated and was correlated
with the nodal status [Table 3]. Positive nodes were seen in 67.5% (135) of cases, of which tumor with distance
from skin less than 0.3 cm show maximum nodal positivity (87 of 135 = 64.4%) and maximum
cases with N2 and N3 disease (66 cases of 135 = 48.8%).
Table 3
Correlation of nodal status with distance of tumor from skin
|
Distance of tumor from skin (cm)
|
Lymph node status
|
Total
|
Total nodes positive (%)
|
Total nodes negative (%)
|
|
N0
|
N1
|
N2
|
N3
|
|
<0.3
|
11
|
21
|
44
|
22
|
98
|
87 (88.7)
|
11(11.3)
|
|
>0.3
|
54
|
24
|
15
|
9
|
102
|
48 (47)
|
54 (53)
|
|
Total
|
65
|
45
|
59
|
31
|
200
|
135 (67.5)
|
65 (32.5)
|
Most significant was the finding that [Table 2] 100% cases with tumor size corresponding in T2 stage with skin invasion either grossly
or microscopically in T3 stage tumors were positive for metastatic deposits in axillary
region and 10/11 cases (90%) in T4 stage were positive. Hence, showing a positive
result to our proposition. One case with T4 stage with negative nodes showed microscopically
medullary type of morphology. Furthermore, tumors in outer upper quadrant were an
independent predictor of axillary lymph node positivity (75.5%). Correlation of nodal
status with Modified Scarf Bloom Richardson grading was also studied [Table 4]. Grade II was associated with maximum nodal positivity percentage (71.2%).
Table 4
Correlation of nodal status with grading of tumor
|
Tumor grading
|
Lymph node status
|
Total
|
Total nodes positive (%)
|
Total nodes negative (%)
|
|
N0
|
N1
|
N2
|
N3
|
|
Grade I
|
2
|
1
|
1
|
0
|
4
|
2 (50)
|
2 (50)
|
|
Grade II
|
15
|
12
|
20
|
5
|
52
|
37 (71.2)
|
15 (28.8)
|
|
Grade III
|
48
|
32
|
38
|
26
|
144
|
96 (66.7)
|
48 (33.3)
|
|
Total
|
65
|
45
|
59
|
31
|
200
|
135 (67.5)
|
65 (32.5)
|
Discussion
Several factors are known to affect the biological behavior of breast cancer. These
include the clinical and demographic features, pathological characteristics, nodal
involvement, and the molecular factors within the breast tumor itself.[13]
The exact role that each of these may have on the biological behavior of breast cancer
is an area of increasing interest, including their role in the regional spread of
the disease. However, their impact on treatment until now continued to be an area
of research interest only.
Although tumor characteristics and molecular markers contribute to the understanding
of breast cancer biology, axillary lymph node status remains one of the most reliable
prognostic factors and is used as a guide for adjuvant breast cancer treatment.[14],[15],[16]
Identifying preoperative predictors of positive nodes helps guide the neoadjuvant
therapy or surgical plan of choice and help patients become better psychologically
prepared for axillary lymph node dissection (ALND) if required.
The three-dimensional lymphatic microanatomy of the breast is not well-known, despite
the many studies reporting on the lymphatic drainage pathways from the breast and
advances in breast sentinel lymphatic mapping particularly the superficial lymphatic
drainage. Several reports have proposed that the dermal lymphatic pathway defines
the clinically relevant breast cancer metastatic pathway and suggest that lymphatic
supply is less abundant or available in the breast parenchyma than that in the superficial
dermal and subdermal layers.[17],[18] This hypothesis has been supported by several studies that investigated sentinel
lymph node biopsy (SLNB) methods.
Although SLNB is replacing ALND for axillary staging and is emerging as the new standard
of care, there is a lack of standardized methodology for the procedure.
Axillary lymph node biopsy remains the best way to evaluate the presence of node metastases.
It is also important in locoregional disease control. However, it is associated with
complications such as lymphedema, shoulder stiffness, breast edema, seroma formation,
upper limb numbness, and brachial plexopathy.[19],[20]
Thus, finding an independent predictor of axillary lymph node positivity is highly
valuable preposition both for the treating surgeon as well as the patient.
However, only a few reports have investigated tumor proximity to the skin and evaluated
its relationship with axillary node metastasis.[17],[21] In this study, breast cancer distance from the skin <3 mm resulted in greater axillary
node metastasis and was highly significant (P < 0.001).
Ansari et al.[21] reported that more superficial tumors are associated with axillary node metastasis
at diagnosis. They reviewed 233 breast cancers in T2 and T3 and found that decreasing
tumor distance from the skin was significantly associated with positive axillary lymph
nodes in a multivariate analysis.
Cunningham et al.[17] reported that tumors closer to the skin are more likely to have metastasis to the
axillary nodes. They reviewed 209 T1 and T2 invasive breast cancer cases and determined
an apparent threshold of approximately 1.4 cm from the skin. None of the cancers with
a distance >1.4 cm (26 cancers) had axillary node metastasis. However, the findings
were based on radiological evaluation, unlike our study.
Chao et al.[18] proposed that palpable tumors are closer to the dermal lymphatics compared with
nonpalpable tumors, and that this explains why palpable tumors more frequently metastasize
to the axillary lymph nodes compared with nonpalpable tumors.
Although tumor palpability is an independent risk factor for axillary node metastasis,
it is insufficient to use as a parameter to predict axillary node metastasis as its
affected by several other factors, including physician subjectivity, tumor size, breast
tumor depth, hardness, ethnicity, body weight, menopausal status, hormone use, and
elasticity of the mass and surrounding tissue.[22],[23]
Siddiqui et al.[6] in multivariate analysis observed that only the tumor size, skin and nipple involvement
and disease in the outer quadrants of the breast were predictive for axillary node
involvement.
Similarly, our study also observed greater axillary lymph node positivity with advanced
tumor stage more so in cases with proximity to overlying skin.
Conclusion
We found the distance of skin from underlying tumor as an independent predictive factor
in for the presence of axillary lymph node metastases. With this information, either
radiologically or intraoperative/postoperation evaluation of mastectomy specimen,
we can select women who are likely to be node negative and give better preoperative
counseling with information to patients regarding the probability of requiring further
axillary dissection. This will empower patients in the participation of the management
of their disease and possibility of follow-up surgery.
Not all cases of duct carcinoma will metastasize to lymph nodes. Even tumors of higher
nuclear grade may be localized. According to literature, the lymph node metastasis
was more commonly associated with tumors of larger size and with obvious lymphovascular
emboli. However, it was also noticed that tumors of smaller size can also present
with Axillary nodal metastasis. Anatomically, dermis of skin and nipple and areola
has a dense network of lymphatics, and tumor close to the skin or nipple and areola
may present with metastasis even with a smaller size. Hence tumor with smaller size
but closer to skin should be managed as a tumor which is potentially capable of metastasis,
and careful examination should be made to evaluate axillary nodal status.
The study is probably the first in Indian population, and more studies need to be
conducted on larger patient groups for more conclusive interpretations and outcome.
